The present study investigated the alteration of protein kinase C (PKC) isoforms in rat liver during the progression of sepsis. Cecal ligation and puncture (CLP) model of polymicrobial sepsis was used, with early and late sepsis referring to those animals sacrificed at 9 and 18 h, respectively, after CLP. The protein contents of various PKC isoforms were quantified by Western blot and densitometric analysis. PKC&agr; activity was performed after immunoprecipitation and assayed based on the incorporation rate of32p from [&ggr;-32p] adenosine triphosphate (ATP) into histone. The distribution of PKC&agr; was evaluated by immunohistochemical staining. The steady state expression of PKC&agr; mRNA was estimated by reverse transcriptase-polymerase chain reaction (RT-PCR). The results indicated that 1) five isoforms (&agr;, &bgr;, &dgr;, ε, ζ) could be detected in normal rat liver. PKC&agr; and &bgr; were predominantly present in the cytosolic fraction, while membrane-associated PKC&dgr; was more prominent than that of cytosolic fraction; 2) the protein content of membrane-associated PKC&agr; was significantly decreased at early (P< 0.05) and late (P< 0.01) sepsis; 3) there was no significant difference of protein contents of PKC-&dgr;, -ε and -ζ between sham-operated and septic rat liver; 4) the activity of membrane-associated PKC&agr; was significantly declined under detection level during sepsis; 5) at both early and late sepsis, the immunohistochemical staining of PKC&agr; was significantly diminished, especially in the nucleus; 6) the RT-PCR product of PKC&agr; mRNA of septic liver was significantly less than the sham-operated liver. These results suggest that inactivation and the suppression of PKC-&agr; gene transcription might be involved in modulating hepatic failure during sepsis.